We propose to evaluate genetic polymorphisms and haplotypes in nucleotide excision repair (NER) genes in relation to the risk for melanoma and non-melanocytic skin cancers (squamous cell carcinoma, SCC; basal cell carcinoma, BCC) among women in the Nurses' Health Study. Because DNA photoproducts directly induced by ultraviolet (UV) are predominantly removed by NER, NER is a major DNA repair pathway mitigating UV genotoxic effects. Despite extensive evidence for the role of NER in the repair of UV-induced DNA damage, the importance of common inherited variations in NER and their interaction with sun exposure in causing skin cancer is relatively unknown. We hypothesize that genetic variations in NER genes confer individual susceptibility to skin cancer, and these genetic variations modify the association between sunlight exposure and the risk of skin cancer. SNPs with potential functional relevance and haplotype-tagging SNPs will be identified from the systematic resequencing data of the NIEHS Environmental Genome Project. We will evaluate these genetic variations in NER genes in relation to skin cancer risk, and assess the potential gene-environment interactions between these polymorphisms and haplotypes, constitutional susceptibility, and sunlight related risk factors. The present application is based on the previously established nested skin cancer case-control study with the Nurses' Health Study, consisting of 219 cases of melanoma, 286 SCC, 300 BCC, and 874 matched controls. We expect to identify about 60 more incident melanoma cases (in the 2000-2002 disease follow-up cycle) and about 160 more incident SCC cases (in the 1998-2002 disease follow-up cycle) in this application. We will have >90% power to detect relative risks of 1.5 or greater for the main effects of most of the genotypes of interest. We will also have substantial power to detect interactions between these genotypes and sunlight exposure. This study will be among the first studies of the association of polymorphisms in candidate NER genes with three major types of skin cancer, and will also assess potential interactions between genotypes and haplotypes and sunlight exposure on skin cancer risk.